Magnesium sulphate (MgSO) given to women in preterm labor reduces cerebral palsy in their offspring but the mechanism behind this protection is unclear, limiting its effective, safe clinical implementation. Previous studies suggest that MgSO is not neuroprotective if administered during or after the insult, so we hypothesised that MgSO induces preconditioning in the immature brain. Therefore, we administered MgSO at various time-points before/after unilateral hypoxia-ischemia (HI) in seven-day-old rats. We found that MgSO treatment administered as a bolus between 6 days and 12 h prior to HI markedly reduced the brain injury, with maximal protection achieved by 1.1 mg/g MgSO administered 24 h before HI. As serum magnesium levels returned to baseline before the induction of HI, we ascribed this reduction in brain injury to preconditioning. Cerebral blood flow was unaffected, but mRNAs/miRNAs involved in mitochondrial function and metabolism were modulated by MgSO. Metabolomic analysis (H-NMR) disclosed that MgSO attenuated HI-induced increases in succinate and prevented depletion of high-energy phosphates. MgSO pretreatment preserved mitochondrial respiration, reducing ROS production and inflammation after HI. Therefore, we propose that MgSO evokes preconditioning via induction of mitochondrial resistance and attenuation of inflammation.

Objectives Depression is common in patients with diabetes, and the use of antidepressants may impair glycaemic control. We assessed the association between antidepressant use and hyper-and hypoglycaemia. Methods Based on spontaneous reports listed in the World Health Organization (WHO) Adverse Drug Reaction Database, a case-control study was conducted. The study base consisted of all adverse drug reactions (ADRs) ascribed to antidepressants, antipsychotics and benzodiazepines between 1969 and 2005. Cases were defined as reported ADRs classified as hyper-or hypoglycaemia and separated in different study populations. All other reports were considered as controls. Exposure to antidepressants was the primary determinant investigated. Benzodiazepines and antipsychotics were chosen as reference groups. Potential confounding factors, namely, age, gender, use of antidiabetic medication, use of hyper-or hypoglycaemiainducing comedication and reporting year, were determined on the index date. Multivariate logistic regression was used to evaluate the strength of the association, which was expressed as reporting odds ratios (RORs) with 95% confidence intervals (95% CI). Results Overall, the use of antidepressants was associated with hyperglycaemia [ROR 1.52 (95% CI: 1.20-1.93)] and of hypoglycaemia [ROR 1.84 (95% CI: 1.40-2.42)]. The association with hyperglycaemia was most pronounced for antidepressants with affinity for the 5-HT 2c receptor, histamine-1 receptor and norepinephrinic (NE) reuptake transporter. The association with hypoglycaemia was most pronounced for antidepressants with affinity for the serotonin reuptake transporter. Conclusion The results of this study strengthen the findings in individual case reports that the use of antidepressants is associated with disturbances in glucose homeostasis.

Germinal matrix hemorrhage (GMH) is a serious complication in extremely preterm infants associated with neurological deficits and mortality. The purpose of the present study was to develop and characterize a grade III and IV GMH model in postnatal day 5 (P5) rats, the equivalent of preterm human brain maturation. P5 Wistar rats were exposed to unilateral GMH through intracranial injection into the striatum close to the germinal matrix with 0.1, 0.2, or 0.3 U of collagenase VII. During 10 days following GMH induction, motor functions and body weight were assessed and brain tissue collected at P16. Animals were tested for anxiety, motor coordination and motor asymmetry on P22–26 and P36–40. Using immunohistochemical staining and neuropathological scoring we found that a collagenase dose of 0.3 U induced GMH. Neuropathological assessment revealed that the brain injury in the collagenase group was characterized by dilation of the ipsilateral ventricle combined with mild to severe cellular necrosis as well as mild to moderate atrophy at the levels of striatum and subcortical white matter, and to a lesser extent, hippocampus and cortex. Within 0.5 h post-collagenase injection there was clear bleeding at the site of injury, with progressive increase in iron and infiltration of neutrophils in the first 24 h, together with focal microglia activation. By P16, blood was no longer observed, although significant gray and white matter brain infarction persisted. Astrogliosis was also detected at this time-point. Animals exposed to GMH performed worse than controls in the negative geotaxis test and also opened their eyes with latency compared to control animals. At P40, GMH rats spent more time in the center of open field box and moved at higher speed compared to the controls, and continued to show ipsilateral injury in striatum and subcortical white matter. We have established a P5 rat model of collagenase-induced GMH for the study of preterm brain injury. Our results show that P5 rat pups exposed to GMH develop moderate brain injury affecting both gray and white matter associated with delayed eye opening and abnormal motor functions. These animals develop hyperactivity and show reduced anxiety in the juvenile stage.

We have established a postnatal day 4 rat model of HI for the study of preterm brain injury. MgSO provides a marked preconditioning protection both in postnatal day 4 rats and in postnatal day 5 mice.